In the delivery of certain slightly water-soluble drugs intended to act by contact with the mucosal surface of the gastrointestinal tract (hereinafter referred to as the GI tract) without substantial absorption therethrough into the blood stream, the problem of insufficient adherence and dwell time are often encountered. Drugs, such as antacids, antimicrobial and antifungal agents tend to pass through the GI tract without providing sufficient local preventive/active effects.
Accordingly, there is a need to provide oral GI formulations that are safe, efficacious and have sufficient dwell or contact time with the GI mucosa. Such formulations should have excellent mucosal coating properties for both the upper and lower GI tract, i.e., they should have mucoadhesive or bioadhesive properties that enable the entire GI tract to be coated. There also exists a need to provide formulations to specific regions within the GI tract. Since the slightly water-soluble drugs do not by themselves possess such bioadhesive or mucoadhesive properties, the formulations containing them must provide the same.
The identification of surface active stabilizers with bioadhesive or mucoadhesive properties that enable coating of the entire GI tract or specific regions within the GI tract with therapeutic agents has not been reported to date.
It is common medical practice to employ barium sulfate formulations to image the GI tract of patients. Barium sulfate can be given either orally or rectally to visualize the stomach and small intestine or rectally to visualize the large intestine. Barium sulfate is usually administered as a suspension that has limited stability even with the addition of stabilizers. As such, it often forms clumps that yield resultant radiopaque areas on X-ray films and provides for poor patient acceptability characteristics. Poor patient acceptability characteristics include palatability, patient discomfort during and after administration and prolonged constipation of the patient. Barium sulfate also shows poor affinity for coating the GI mucosa and consequently the patient is often manipulated or rotated to ensure the barium sulfate suspensions coat the gastric mucosa. Nevertheless, segments of the GI tract are often obscured or are not adequately coated, necessitating repeated examinations to achieve satisfactory imaging results.
Bioadhesion is usually achieved by interaction of either a synthetic or natural polymeric substance with the mucosal membranes of the GI tract. Such technology has been employed to enhance drug delivery by increasing the transit time of a drug substance in the GI tract and hence promoting an opportunity for enhanced absorption. With regard to the development of water insoluble of poorly water-soluble drug formulations intended to coat the GI tract, it is important to identify mucosal adhesives that coat the GI surfaces and affect diseased or abnormal tissues. Highly charged carboxylated polyanions are good candidates for use as bioadhesives in the GI tract. See, for example: Park, K. and Robinson, J. R., Bioadhesion: Polymers for Orally Controlled Drug Delivery; Method to Study Bioadhesion. Int. J. Pharm., 19, 107 (1984). The formation of a bioadhesive bond between a polymeric substance and the mucosal lining of the GI tract can be visualized as a two step process, i.e., initial contact between the two surfaces and the formation of secondary bonds due to non-covalent interactions. Bioadhesives specific for the GI tract must interact with the mucus layer during attachment. Mucus, a general term for the heterogeneous secretion found on epithelial surfaces of the GI tract, is made of the following components: glycoprotein macromolecules, inorganic salts, proteins, lipids, and mucopolysaccharides. These glycoproteins typically consist of a protein core with carbohydrate side chains. This forms a network of mucus that is a continuous layer covering the GI tract. From a bioadhesive perspective, mucus consists of highly hydrated, cross linked linear, flexible yet random coiled glycoprotein molecules with a net negative charge. Understanding the principals of bioadhesion is the basis for formulating oral or rectal compositions for coating portions of the GI tract. Bioadhesion accounts for the interaction between a biological surface and a biological substance. As noted previously, bioadhesive agents are usually polymeric substances that adhere to tissues by ionic or covalent bonds of by physical attachment. Several theories of bioadhesion have been published including electronic, adsorption, wetting, diffusion, and fracture theories. Bioadhesives bind to membrane surfaces and are retained for various periods of time.
We have discovered a certain class of polymers for promoting site specific bioadhesion or mucoadhesion within the GI tract. The polymers provide for site-specific delivery of medicinal agents within the GI tract. Moreover, the polymers provide for site-specific imaging of the GI tract.
In accordance with the present invention, there is provided an orally/rectally administrable GI formulation containing an effective amount of a water-insoluble or poorly water-soluble therapeutic agent. There is further provided a method for affecting diseased conditions in the GI tract comprising oral or rectal administration to a patient, an effective amount of the above-identified formulation to prevent or cure such diseased conditions. There is further provided a method and formulation for X-ray diagnostic imaging of the GI tract which includes orally or rectally administering to the patient an effective amount of X-ray contrast compositions.